The side effects of chemotherapeutic agents used in the treatment of malignancy and other indications are well known. Among these side effects are alterations in the levels of various blood cells, including neutrophils, platelets and lymphocytes. The results of these effects can be neutropenia, thrombocytopenia and general immune suppression. These side effects are not only unpleasant, but they also restrict the efficacy of cancer therapy and place the subject at serious risk of infection and uncontrolled bleeding.
At the present time, there is little practical remediation for these effects. Typically, the approaches are supportive care, large doses of antibiotics or the administration of growth factors. The administration of growth factors, such as granulocyte colony-stimulating factor (GCSF), granulocyte macrophage colony-stimulating factor (GMCSF), and more newly developed factors such as megakaryocyte growth and development factor (MGDF) and thrombopoietin (TPO) are costly. In addition, they have their own associated negative side effects.
The problems related to current approaches for managing the side effects of chemotherapy and otherwise dealing with suppression of hematopoiesis are solved, at least in part, by the biological activity of certain simple tripeptide compounds which are inhibitors of the various isoenzymes of glutathione S-transferase.
As with many small peptide-based compounds, the formulation of such compounds plays a substantial role in their solubility and efficacy. It is known that lipid formulations (Liposomes as Drug Carriers, ed. G. Gregoriadis, John Wiley and Sons, 1988) and emulsions or lipid microspheres (Cummings, J. et. al. Expert Opin. Ther. Pat. (1998), 8(2), 153; Takenaga, M. Adv. Drug Delivery Rev. (1996), 20(2,3), 209; Yamaguchi, T. Adv. Drug Delivery rev. (1996), 20(2,3), 117; Mizushima, Y. EP 0432697A2; Kraft, M. WO 98/05301) can be used as suitable pharmaceutical carriers that enhance solubility, modulate pharmacokinetic behavior, modify biodistribution, and protect compounds from enzymatic degradation. Increasing the lipophilicity of the compound oftentimes aids in the formulatability of compounds in emulsions and liposomes. Esters containing longer carbon chains or other lipophilic groups can, thus, be used to tailor compounds to maximize solubility.
A liposome is a completely closed lipid bilayer membrane which defines a closed aqueous compartment. Liposomes are microscopic delivery vesicles made, in part, from phospholipids which form closed, fluid-filled spheres when mixed with water. Liposomes may be either unilamellar, comprised of one lipid bilayer membrane, or multilamellar, comprised of more than bilayer. Liposomes have the potential of providing controlled release of the administered drug over an extended period of time and of reducing toxic side effects of the drug by limiting the free concentration of the active agent in the bloodstream. Liposomes can also alter the tissue distribution and uptake of drugs, and the altered tissue distribution can significantly increase the therapeutic effectiveness of the drug.
PCT application W095/08563, published Mar. 30, 1995, and PCT/US94/10797 disclose the tripeptide compounds which are analogs of glutathione. They are generally inhibitors of glutathione S-transferase activity, and the various compounds contained in this group show diverse specificities with respect to glutathione S-transferase isoenzymes. Disclosed in these patents are symmetrical esters of 1 to 10C units, with the preferred embodiment as the diethyl ester.